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Enhanced retention of cytosine arabinoside and its metabolites and synergistic cytotoxicity by sequential treatment with dipyridamole in L5178Y leukemia

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Summary

Sequential treatment of murine leukemia L5178Y with cytosine arabinoside (ara-C) followed by dipyridamole (DP) resulted in synergistic cytotoxicity. Viability of cells exposed to 1 µM ara-C for 4 h was 88% of control values, but if DP was included in the cloning medium, cell viability was reduced to only 30%. When cells exposed to 1 µM ara-C were resuspended in ara-C-free medium containing 10 µM DP, intracellular ara-C and its metabolites were retained for a significantly longer period than when cells were resuspended in drug-free medium. At 4 h after resuspension in ara-C-free medium, total intracellular [3H] was 1.9 pmol/106 cells in control cells but amounted to 6.2 pmol/106 cells in DP-treated cells. Unchanged ara-C was 5.5-fold higher in the DP-treated cells. Presumably because of its effect on the concentration of intracellular ara-C, DP increased the half-life for ara-CTP from 97 to 250 min. Ara-CDP-choline declined with a half-life of 76 min on the transfer of cells to control medium, but levels of this metabolite remained constant or increased slightly in cells transferred to medium containing DP. After 4 h in ara-C-free medium with DP, [3H]-ara-C incorporated into the acid-insoluble fraction was 140% of the level attained when cells were transferred to control medium. The increased levels of ara-C metabolites presumably represent the basis for the enhancement of ara-C cytotoxicity by sequential DP treatment.

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Abbreviations

ara-C:

1-β-d-arabinofuranosylcytosine, cytosine ara-binoside

ara-CTP:

ara-C 5’triphosphate

ara-CDP-choline:

ara-C diphosphocholine

ara-C-DNA:

ara-C incorporated into DNA

DP:

dipyridamole, Persantin, 2,2′,2″,2′′′-(4,8-dipiperidinopyrimido (5,4-d) pyrimidine-2,6-dinitrilo) tetraethanol

PBS:

phosphate-buffered saline

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Authors and Affiliations

  1. Cancer Center of Wake Forest University, 27103, Winston-Salem, NC, USA

    Jin-Long Yang, J. Courtland White & Robert L. Capizzi

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  1. Jin-Long Yang
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  2. J. Courtland White
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  3. Robert L. Capizzi
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Additional information

This research was supported by grant CH-35H from the American Cancer Society and grant CA12197 from the National Institutes of Health

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Yang, JL., Courtland White, J. & Capizzi, R.L. Enhanced retention of cytosine arabinoside and its metabolites and synergistic cytotoxicity by sequential treatment with dipyridamole in L5178Y leukemia. Cancer Chemother Pharmacol 26, 135–138 (1990). https://doi.org/10.1007/BF02897259

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  • DOI: https://doi.org/10.1007/BF02897259

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